Hypothermia is a condition of temperature-regulating organisms wherein the core body temperature becomes reduced below the normal range. Hypothermia has been used clinically for more than forty years to protect bodily organs from various pathophysiological insults, including ischemic insults such as cardiac arrest, hemorrhage, hypergravity, and hypoglycemia, and to reduce the toxicity of various drugs and environmental toxicants (see Gordon (2001) Emerg Med J 18:81-89). While the precise mechanisms responsible for the therapeutic effects of hypothermia are not fully understood, hypothermia causes a general reduction in cellular metabolism (Polderman (2008) Lancet 371:1955-1969). This reduction in cellular metabolism during hypothermia is especially beneficial to highly aerobic organs, such as the brain and heart, under ischemic conditions because it leads to a reduction in the demand for oxygen.
Currently, forced hypothermic methods are used for therapeutic hypothermia. Forced hypothermia involves the use of external and/or endovascular cooling methods to extract heat from the body to reduce the body temperature below the normal set-point temperature. External cooling methods consist of immersion of a subject in a cool bath or application of blankets or pads with cooled water circulating through channels in the walls of the blanket or pad to the skin of a subject. Other external methods include wetting of the skin or hair of the subject, cooling the air surrounding the subject, and blowing air across the subject's skin. Endovascular cooling generally involves the intravenous administration of a cool saline solution.
To combat the lowering body temperature during forced hypothermia, the body uses various thermoregulatory effector mechanisms (i.e. shivering, non-shivering thermogenesis, peripheral vasoconstriction, and release of stress hormones) to generate heat and reduce heat loss (Frank et al. (1997) Am J Physiol 272:R557-R562). These thermoeffector responses are undesirable because the responses impede the efficacy of the cooling mechanism to reach the target temperature and are stressful and uncomfortable for the patient. Subjects undergoing forced hypothermia must be chemically sedated and paralyzed to reduce the stress on the patient from these thermoeffector responses. In addition, the stress of lowering body temperature from forced hypothermia transiently increases oxidative stress which may have an impact on ischemic organs (Katz et al. (2004) Brain Res 1017:85-91). In those patients with acute brain injuries, for example, hypothermia has a limited therapeutic window of opportunity and any delay and physiological stress that arises in reaching the target temperature will most likely have a negative impact on outcome (Clifton (2004) Curr Opin Crit Care 10:116-119; Ginsberg (2003) Stroke 34:214-223; Kuboyama et al. (1993) Crit Care Med 21:1348-1358). Therefore, other methods of inducing hypothermia for therapeutic purposes that result in a rapid induction of hypothermia with minimal stress on the patient are needed.